Green Approach To Synthesize Crystalline Nanoscale ZnII

Mar 15, 2018 - Synopsis. A green synthetic route has been developed to synthesize biologically relevant crystalline nanoscale coordination polymers. I...
0 downloads 19 Views 8MB Size

Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Green Approach To Synthesize Crystalline Nanoscale ZnIICoordination Polymers: Cell Growth Inhibition and Immunofluorescence Study Somali Mukherjee,† Sumi Ganguly,† Krishnendu Manna,‡ Sanchaita Mondal,‡ Supratim Mahapatra,‡ and Debasis Das*,† †

Department of Chemistry, University of Calcutta, 92, A. P. C Road, Kolkata-700009, India Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata-700032, India

S Supporting Information *

ABSTRACT: Five new coordination polymers (CPs) namely, [{Zn(μ2H2O)0.5(5N3-IPA)(2,2′-bpe)}]∞ (1), [{Zn(μ2-H2O)0.5(5N3-IPA)(1,10phen)}]∞ (2), [{Zn(5N3-IPA)(1,2-bpe)}]∞ (3), [{Zn(5N3-IPA)(1,2bpey)}]∞ (4), and [{Zn(H2O)(5N3-IPA)(4,4′-tme)}(H2O)0.5]∞ (5) (5N3-H2IPA = 5-azidoisophthalic acid, 2,2′-bpe= 2,2′-bipyridine, 1,10phen = 1,10-phenanthroline, 1,2-bpe = 1,2-bis(4-pyridyl)ethane, 1,2bpey = 1,2-bis(4-pyridyl)ethylene, 4,4′-tme = 4,4′-trimethylenedipyridine), have been synthesized based on a mixed ligand approach adopting a solvothermal technique. Depending upon the intrinsic structural flexibility of the bis-pyridyl coligands, interesting structural topologies have also been observed in the resulting CPs: Sra SrAl2 type topology for 3 and a 3-fold interpenetrated dmp topology for 4. A green hand grinding technique has been implemented to reduce the particle size of the CPs to generate nanoscale CPs (NCPs). SEM studies of NCPs reveal the formation of square and spherical particles for NCP 1 and 2, respectively, and nano rod for NCP 3, 4, and 5. Remarkably, when scaled down to nano range all the NCPs retain their crystalline nature. The cytotoxic activity of the NCPs (15) has been studied using human colorectal carcinoma cells (HCT 116). Significant cell death is observed for NCP 2, which is further corroborated by cell growth inhibition study. The observed cell death is likely to be due to mitochondrial-assisted apoptosis as is evident from immunofluorescence study.

INTRODUCTION Coordination polymers (CPs) are infinitely extended crystalline solids constructed from metal ions and multitopic organic linkers.1−4 Since the first report of the crystal structure in the 1980s,5 the research activities pertaining to CPs have gained tremendous impetus because of their potential applicability in gas adsorption6−8 and storage,9−11 separation,12−17 catalysis,18−25 sensing,26−32 and nonlinear optics33,34 etc. CPs usually exhibit very low solubility in common organic solvents which limits their usability in a number of desirable biological applications such as imaging, drug delivery, diagnosis of cancer, etc. A possible way out is to reduce the particle size of the CPs to nanoscale regime so that the nanoscale CPs (NCPs) could be easily administered within the cell. NCPs can be prepared by a number of methods such as nanoprecipitation,35 microemulsion,36 surfactant mediated synthesis,37 and solvothermal38 and sonochemical,39 synthesis, etc. Most of these methods are highly complicated, and the size as well as morphology of the synthesized nanoparticles depends on the precursor ratio and reaction conditions. However, much simpler techniques with fewer or no additives and using ordinary solvent systems are © XXXX American Chemical Society

highly desirable in order to design and fabricate multifunctional NCPs. Over the past few years, significant research efforts have been devoted to study the clinical applications of materials with nanometer scale size because of their tailorable surface chemistry, high drug loading and release, improved biocompatibility and enhanced permeability through cell membranes, etc.40,41 The majority of nanoparticles used for biological applications to date are either purely inorganic or purely organic in nature.42−46 NCPs are hybrid materials that combine the beneficial features of inorganic and organic nanoparticles.47−53 NCPs possess several advantageous features over existing nanosystems, such as the size, shape, and composition of NCPs could be easily tuned via synthetic manipulations, highly porous and oriented structures for efficient loading properties, etc. Moreover, the NCPs are intrinsically biodegradable since the metal−ligand bonds are labile in nature and thus could be easily excreted from the Received: January 27, 2018


DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry Scheme 1. Preparation of the CPs 1−5a


The optical images of the mounted single crystals are shown.

Table 1. Crystallographic Data and Refinement Parameters for CPs 1−5

CCDC Number empirical formula Fw crystal size/mm crystal system space group a/Å b/Å c/Å α/deg β/deg γ/deg V/Å3 Dcalcd/g cm−3 Z F(000) μ/mm−1 Mo Kα radiation T/K Rint Range of h,k,l θmin/max/deg Reflections collected/unique/ observed [I > 2σ(I)] Data/restraints/ parameters GOF on F2 Final Rindices[I > 2σ(I)] Rindices(all data)






1587101 C36H24N10O9Zn2 871.43 0.22 × 0.11 × 0.05 monoclinic C2/c 24.905(4) 8.6572(12) 16.110(2) 90 94.788(7) 90 3461.2(9) 1.672 4 1768.0 0.202 λ=0.71073 Å 296(2) 0.0300 −29/29,−10/10, −14/19 2.492/24.815 19662/2987/2582

1587102 C40H24N10O9Zn2 919.47 0.50 × 0.30 × 0.16 monoclinic C2/c 24.356(3) 9.5565(12) 15.2665(19) 90 94.996(3) 90 3539.9(8) 1.725 4 1864.0 0.202 λ=0.71073 Å 296(2) 0.0227 −29/29,−11/10,−18/18 2.616/25.746 21502/3362/3133

1587103 C20H15N5O4Zn 454.76 0.27 × 0.20 × 0.12 monoclinic C2/c 14.5141(12) 15.7728(14) 16.7098(15) 90 104.337(3) 90 3706.2(6) 1.630 8 1856.0 0.202 λ=0.71073 Å 296(2) 0.0664 −17/17,−19/18,−20/20 1.940/25.878 22467/3573/2711

1587104 C20H13N5O4Zn 452.74 0.40 × 0.19 × 0.07 monoclinic P21/n 7.8552(18) 17.220(4) 15.120(3) 90 94.542(7) 90 2038.7(8) 1.475 4 920.0 0.202 λ=0.71073 Å 296(2) 0.0944 −8/9,−21/19,−16/18 1.796/25.757 14756/3798/1944

1587105 C42H40N10O11Zn2 991.62 0.30 × 0.25 × 0.07 triclinic P1̅ 10.2651(19) 10.614(2) 11.696(2) 67.541(6) 80.987(6) 62.407(5) 1043.4(3) 1.578 1 510.0 0.202 λ=0.71073 Å 296(2) 0.0221 −12/12,−13/12,−14/14 2.239/26.054 13523/4055/3590






1.100 R1 = 0.0659

1.017 R1 = 0.0249

1.069 R1 = 0.0487

1.045 R1 = 0.0975

1.053 R1 = 0.0281

wR2 = 0.1278 R1 = 0.0766 wR2 = 0.1348

wR2 = 0.0694 R1 = 0.0270 wR2 = 0.0709

wR2 = 0.1194 R1 = 0.0656 wR2 = 0.1284

wR2 = 0.2166 R1 = 0.1689 wR2 = 0.2495

wR2 = 0.0692 R1 = 0.0340 wR2 = 0.0724


DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry

Figure 1. Crystal structure illustration of 1: (a) 2D corrugated sheet network; (b) left-hand helical framework; (c) right-hand helical framework; (d) topological representation of 3-c uninodal network.

2,2′-bipyridine (2,2′-bpe), and one-half occupied coordinated water molecule (located on a crystallographic 2-fold axis) in the asymmetric unit. The central ZnII adopts a distorted square pyramidal geometry (τ5 = 0.49)55,56 where two basal sites are chelated by two N atoms coming from 2,2′-bpe moiety and the other two sites are coordinated to carboxylate O atoms of isophthalate moiety. The axial position of the distorted square pyramid is occupied by the O atom coming from a coordinated μ2 bridging water molecule (Table S9, Table S10, and Figure S25). Each 5N3-IPA moiety coordinates two metal centers in the η1-binding fashion. In the crystal structure four symmetry related ZnII ions are bridged by two water molecules and two 5N3-IPA moieties creating a closed loop which is further propagated in 2D via extended coordination through the carboxylate moieties of 5N3-IPA. The overall structure may be best described as a 2D corrugated sheet that runs parallel to the ac plane. A closer inspection of the crystal structure reveals that each 2D corrugated sheet is composed of right-hand and lefthand helixes as depicted in Figure 1. Such 2D sheets are further stabilized via offset π···π interaction between two chelating 2,2′bipyridine rings. Topological analysis has been carried out by using TOPOS.57−61 The results show that 1 displays a 3-c uninodal net with Schläfli symbol {4^2.6} (Figure 1). [{Zn(μ2-H2O)0.5(5N3-IPA)(1,10-phen)}]∞ (2). The crystal structure analysis of 2 shows that this compound is isomorphous with 1 as revealed by the identical space group (monoclinic C2/c), near identical cell dimensions, and similar coordination geometry around the central ZnII atom (Table S11, Table S12, and Figure S26 in the Supporting Information). The only difference is that in this case 1,10-phenanthroline chelates the metal center instead of 2,2′-bipyridine. The asymmetric unit of 2 is composed of one ZnII, one symmetry independent 5-azidoisophthalate (5N3-IPA), one 1,10-phenanthroline (1,10-phen), and one-half occupied coordinated water molecule located on a crystallographic 2-fold axis. As observed in the case of 1, the central ZnII adopts a distorted square pyramidal geometry. Two basal sites of the distorted square pyramid are occupied by two N atoms of 1,10-phen coligand, and the other two sites are coordinated with carboxylate O atoms coming from two different 5N3-IPA. The apical site is occupied by a coordinated water molecule. The overall structure may be best described as a 2D corrugated sheet network (Figure 2). However, this compound exhibits excellent fluorescence activity owing to the offset π···π interaction

system after its biofunction. Keeping these points in mind, we set out to develop a series of NCPs derived from 5azidoisophthalic acid (5N3H2-IPA), various N-donor coligands such as 2,2′-bipyridine (2,2′-bpe), 1,10-phenanthroline (1,10phen), 1,2-bis(4-pyridyl)ethane (1,2-bpe), 1,2-bis(4-pyridyl)ethylene (1,2-bpey), 4,4′-trimethylenedipyridine (4,4′-tme), and Zn(NO3 ) 2 . While the dicarboxylate 5N 3 -IPA will coordinate with the metal ion to create an extended framework, the bis-pyridyl coligand is expected to make the CPs fluorescence active. Moreover the presence of free azide functionalities in the framework gives tremendous stability to the colloidal suspensions via electrostatic interactions.54 ZnII has been purposefully chosen as a metal center because of its biogenic nature. Solvothermal techniques have been adopted to synthesize five coordination polymers (Scheme 1), namely, [{Zn(μ 2 -H 2 O) 0.5 (5N 3 -IPA)(2,2′-bpe)}] ∞ (1), [{Zn(μ 2 H2O)0.5(5N3-IPA)(1,10-phen)}]∞ (2), [{Zn(5N3-IPA)(1,2bpe)}]∞ (3), [{Zn(5N3-IPA)(1,2-bpey)}]∞ (4), and [{Zn(H2O)(5N3-IPA)(4,4′-tme)}(H2O)0.5]∞ (5). Hand grinding of CPs 1−5 without using any solvent or chemicals leads to lowering the size to the nano regime (NCPs 1−5). SEM analyses reveal exciting crystalline morphologies, square and spherical for NCP 1 and 2, respectively, and nano rod type for NCP 3, 4, and 5. After successful synthesis all the NCPs are subjected to biological studies using human colorectal carcinoma cell lines (HCT 116). NCP 2 was found to be most suitable for antiproliferative studies since it exhibits the highest cell death among all other NCPs (1−5). Furthermore, immunofluorescence study has been performed to unveil the cell death mechanism.

RESULTS AND DISCUSSION Crystal Structure Description. Single crystals of all the CPs 1−5 were harvested under solvothermal conditions (see Experimental Section for details) and subjected to SXRD analyses. The crystal data and refinement parameters are given in Table 1. The ORTEP views, the selected bond angles and bond lengths, and the hydrogen bonding parameters of the CPs are provided in the Supporting Information. Various coordination modes of 5N3-IPA observed in different CPs are summarized in Table S8 in the Supporting Information. [{Zn(μ2-H2O)0.5(5N3-IPA)(2,2′-bpe)}]∞ (1). This compound crystallizes in the monoclinic C2/c space group with one ZnII, one symmetry independent 5-azidoisophthalate (5N3-IPA), one C

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry

Literature reports suggest that there are only a handful of CPs reported that exhibit this kind of topology (Figure 3).62 [{Zn(5N3-IPA)(1,2-bpey)}]∞ (4). Single crystal structure analysis shows that 4 crystallizes in the monoclinic P21/n space group. The asymmetric unit contains one ZnII atom, one symmetry independent 5N3-IPA moiety, and two half occupied 1,2-bis(4-pyridyl)ethylenes (1,2-bpey) situated on a crystallographic inversion center. The central ZnII atom exhibits a distorted tetrahedral geometry (τ4 = 0.84) where two sites of the tetrahedron are occupied by carboxylate O atoms of two symmetry independent 5N3-IPA moieties and the other two sites are coordinated with N atoms of two 1,2-bpey coligands (Table S15, Table S16, and Figure S28 in the Supporting Information). In the crystal structure the carboxylate ligand binds two metals in η1-binding fashion. The carboxylate ligand and the bis-pyridyl coligand bridge the adjacent ZnII centers creating a 2D hexagonal architecture. Further extended coordination via carboxylate and bis-pyridyl coligand creates a 3D network with dimensions 14.54 Å × 17.23 Å. Three such individual 3D networks are further interpenetrated presumably to occupy the huge space generated within each 3D network. A better insight of the crystal structure has been achieved by TOPOS analysis which reveals that 4 exhibits an unusual kind of 3-fold interpenetrated dmp topology with Schläfli symbol {6^5.8} (Figure 4). This kind of topology is very rare for CPs as revealed by the literature reports.63 [{Zn(H2O)(5N3-IPA)(4,4′-tme)}(H2O)0.5]∞ (5). X-ray structure analysis reveals that this compound crystallizes in the triclinic P1̅ space group and its asymmetric unit contains one ZnII ion, one symmetry independent 5N3-IPA moiety, one 4,4′trimethylenedipyridine (4,4′-tme) coligand, one coordinated water molecule, and a half occupied lattice occluded water molecule situated on an inversion center. The central ZnII atom adopts a distorted trigonal bipyramidal geometry (τ5= 0.60) where two basal sites are occupied by carboxylate O atoms coming from two symmetry independent 5N3-IPA ligands and one pyridyl N atom from 4,4′-tme moiety. One of the axial sites is occupied by a coordinated water molecule, and the other site is occupied by a pyridyl N atom of 4,4′-tme moiety (Table S17, Table S18 and Figure S29 in the Supporting Information). Each 5N3-IPA ligand coordinates to the metal center in η1-binding fashion, creating a one-dimensional chain. Each one-dimensional metal carboxylate chain has been bridged by a 4,4′-tme

(center of gravity distance 3.62 Å) in 1,10-phen moieties (vide inf ra).

Figure 2. 2D corrugated sheet framework of 2 with offset π···π interaction.

[{Zn(5N3-IPA)(1,2-bpe)}]∞ (3). 3 belongs to the monoclinic C2/c space group. The asymmetric unit is composed of one fully occupied ZnII center, one symmetry independent 5N3-IPA moiety, and two half occupied 1,2-bis(4- pyridyl)ethane (1,2bpe) moieties, one located on a crystallographic inversion center and the other situated on a 2-fold axis. The central metal ion adopts a five coordinated distorted square pyramidal geometry (τ5 = 0.11) where three basal sites are occupied by carboxylate O atoms coming from the 5N3-IPA ligand and the fourth site is coordinated to the pyridyl N atom of the 1,2-bpe coligand. The axial site is occupied by the N atom coming from the other symmetry independent 1,2-bpe moiety (Table S13, Table S14, and Figure S27 in the Supporting Information). Each 5N3-IPA coordinates with two ZnII atoms via η1- and η2binding fashion. Due to conformational flexibility, two symmetry independent 1,2-bpe coligands bind to the metal center in completely different conformations with dihedral angle 55.76° (bent conformation) and 180° (linear conformation). This kind of coordination mode of the bis-pyridyl coligands leads to the formation of a meso helical framework in 3 which is further extended in 2D via extended coordination through dicarboxylate (5N3-IPA) ligand. Such 2D layers are further propagated in 3D by another 1,2-bpe and carboxylate ligand. A better insight of the crystal structure has been achieved by TOPOS analysis which revealed that 3 exhibits sra SrAl2 type topology with Schläfli symbol {4^2.6^3.8}.

Figure 3. Crystal structure illustration of 3: (a) meso helical framework formed by coordination through 1,2-bpe moiety and ZnII; (b) crystal packing viewed along the crystallographic c axis, (c) topological representation of the 4-c sra SrAl2 type topology. D

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry

Figure 4. Crystal structure illustration of 4: (a) hexagon type network; (b) 3D network with dimension 14.54 Å × 17.23 Å; (c) topological representation of 3-fold interpenetrated dmp type topology.

develop a simple and convenient method of preparing crystalline nanoscale CPs. Interestingly, for single crystals of the CPs 1−5 when subjected to a mechanical grinding in a mortar and pestle for about 30 min, crystalline nanoscale CPs are obtained. The crystalline nature of the nanoscale materials is confirmed by powder X-ray diffraction (PXRD) studies, and it is also noticed that the PXRD pattern of the nanoscale compound matched perfectly well with the simulated and bulk PXRD patterns of the corresponding CPs (Figure S6−S10 in Supporting Information). The FT-IR spectra of the nanoscale CPs also matched well with the as synthesized CPs, suggesting similar metal−ligand connectivities in the nano state (Figure S1−S5 in Supporting Information). Energy dipersive X-ray (EDX) spectrometry studies also support identical chemical composition of NCPs as that of the mother CPs (Figure S20− 24 and Table S3−S7 in Supporting Information). The formation of the nanostructures has been further confirmed by scannig electron microscopy (SEM) studies that are obtained by drop-casting a DMSO-dispersed solution of the NCPs on a glass surface. NCP 1 and 2 adopt almost square and spherical morphologies in order to minimize the interfacial free energy between the particle and the solvent molecules. Remarkably, NCP 3, 4, and 5 exhibit nanorod type morphology (Figure 6). The formation of well-defined structural morphologies in NCPs (3, 4, and 5) might be due to the predominence of crystal lattice energy over the particle−solvent interactions. Dynamic light scattering (DLS) studies are carried out to prove further the nanostucture formation. The results show that the hydrodynamic radius of all the CPs falls in the nano regime (∼100−370 nm, Figure S17 in the Supporting Information). Photoluminescence Studies of Nanoscale Coordination Polymers (NCPs). Having successfully prepared NCPs, their photophysical properties are evaluated. In a typical experiment a DMSO dispersed solution of NCPs is subjected to UV−vis studies (Figure S16). The photoluminescence responses of all the NCPs are measured in solution and solid phase and the observed spectra are depicted in Figure 7 and Figure S19, respectively. It is obvious from those figures that all NPCs are potential luminescent materials and their photoluminescence properties are presumably due to the charge transfer transitions between the metal center and the ligand. Quantum yield calculations (Table S1) and Figure 7 clearly suggest that NCP 2 exhibits the highest photoluminescence efficiency among the synthesized NCPs. The offset π···π stacking interaction present between the adjacent 1,10-phen moieties as is evident by the crystal structure of NCP 2 (Figure

moiety creating a 2D grid network. Such 2D sheets are further packed in parallel fashion sustained by the O−H···O hydrogen bonding interactions, and the interstitial space has been occupied by a lattice occluded disordered water molecule. Topological analysis has been carried out by considering mononuclear ZnII centers as nodes. The results show that 5 exhibits a 4-c uninodal sql topology with Schläfli symbol {4^4.6^2} (Figure 5).

Figure 5. Crystal structure illustration of 5: (a) 2D grid network with interstitial space occupied by disordered water molecules; (b) topological representation of 4-c sql topology.

Preparation of Nanoscale Coordination Polymers (NCPs). Materials with nanometer size scale often exhibit amorphous nature which prohibits a detailed understanding of these systems at the molecular level. Thus, designing crystalline nanoscale material is highly important since the intrinsic structural regularity of the crystalline class allows an exact understanding of their composition. Therefore, we aim to E

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry

NCP Induced Reduction in Cell Viability of HCT 116 Cells. To evaluate the cytotoxic effect of NCPs (1−5), MTT assay was carried out using human colorectal carcinoma cells (HCT 116). Different concentrations of NCPs (5, 10, 20, 40, 80, and 100 μg/mL) were used to screen the cytotoxic activity as well as to determine the IC30, IC50, and IC70 at which 30%, 50%, and 70% cell death occurred at 24 h. Figure 8 depicts a

Figure 8. Assessment of cell viability using MTT assay. Cells were treated with different concentrations (5, 10, 20, 40, 80, and 100 μg/ mL) of NCP (1−5) for 24 h followed by cytotoxicity evaluation. Values are presented as mean ± SEM (n = 5).

Figure 6. SEM micrographs: (a) NCP 1 (Scale bar: 200 nm); (b) NCP 2 (Scale bar: 100 nm); (c) NCP 3 (Scale bar: 200 nm); (d) NCP 4 (Scale bar: 200 nm); and (e) NCP 5 (Scale bar: 100 nm).

marked decrease in cell viability when treated with NCPs in a dose-dependent manner. This result also showed that significant cell death was evident at 24 h when treated with NCP 2 compared to other NCPs. The IC30, IC50, and IC70 of 2 were 0.57, 25.56, and 50.55 μg/mL, respectively, which were much lower with respect to the corresponding values of the other NCPs (Table S2 in the Supporting Information). Moreover, its particle size is ∼100 nm, which is perfectly suitable for any parental administration (subcutaneous or intravenous injection). Particle size and fluorescence activity make NCP 2 the best candidate to pursue its bioactivity. However, before we proceed further with mechanistic investigation of cell death, it is necessary to check the stability of NCP 2 under physiological conditions. In order to establish the biostability, a time dependent DLS (Figure S18 in the Supporting Information) and SEM studies were carried out using a colloidal suspension of NCP 2 in a phosphate buffered saline solution (PBS) (Figure 9). Moreover to check the structural integrity of the NCP 2 in physiological conditions, PXRD has been performed after incubation for 72 h in PBS (Figure S7 in Supporting Information). The results indicate that NCP 2 is remarkably stable under physiological conditions (particle size ∼143 nm). Aggregate formation in colloidal suspension is prevented presumably by the electrostatic interactions between the noncoordinated azide functionalities in the framework and the phosphate group of the PBS buffer.54 The aforesaid discussion clearly points out that NCP 2 is most suitable for further biological studies because of its highest cytotoxic activity. Moreover, its smaller particle size and appreciable biostability prompted us to investigate the mechanism of cytotoxic activity.Thus, a dose of 25 μg/mL of NCP 2 was chosen for the further study to evaluate the mechanism underlying the cellular death. NCP 2 Induced Modulation of Mitochondrial Dependent Apoptosis in HCT 116 Cells. To investigate the

Figure 7. Photoluminescence spectra of NCPs (1−5) dispersed in DMSO (Inset: Optical images of the DMSO dispersed solution of various NCPs under UV light).

2) is likely to be responsible for its prominent luminescence activity. Biological Studies. The foregoing discussions revealed that we are largely successful in preparing crystalline NCPs using a simple mechanical grinding method. The structural regularity of the single crystal phase is completely retained in the NCPs (1− 5) as suggested by the PXRD patterns (Figure S6−S10 in the Supporting Information). The next step is to evaluate the suitability of these compounds for biomedical applications. Since all the CPs are extremely insoluble in common organic solvents, the possibility of leaching of ZnII ions in biological medium could be easily ruled out. The cytotoxicity of all the NCPs (1−5) is checked by MTT (3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide) assay. F

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry

minimize site-specific cell migration as well as trigger cell death (Figure 11).

Figure 11. Assessment of cell migration inhibition. Scratch wound healing assay was performed to examine the effects of NCP 2 treatment in 12 and 24 h.

Figure 9. Morphology of NCP 2: (a) before incubation with PBS; (b) after 24 h; (c) after 72 h of dispersion in PBS buffer.

correlation between cytotoxicity and mitochondrial-dependent apoptosis in the case of NCP 2 induced cellular death, immunofluorescence was used to detect the protein expression level related to the apoptosis, namely Bcl2 and Bax. Numerous scientific reports64,65 demonstrated that mitochondrial-dependent apoptosis is regulated by a plethora of anti- and proapoptotic proteins. Immunofluorescence analysis revealed a marked suppression in antiapoptotic Bcl2 as well as an increase in pro-apoptotic Bax expression when treated with 25 μg/mL of NCP 2 as evident from intensity analysis of the relative fluorescence of FITC and PE (Figure 10). The increased level

CONCLUSION The research results described in this article represent a novel approach toward designing a new series of crystalline nanoscale materials. In this context five new CPs have been synthesized and thoroughly characterized using various physicochemical techniques. An easy, time saving, and green process (without using any solvent) has been adopted to produce the NCPs wherein the composition and structural regularity of the as synthesized CPs remain intact. The utility of the NCPs has been demonstrated by studying their cytotoxic effects on human colorectal carcinoma cell lines. Further elucidation of the cell death mechanism via immunofluorescence study reveals that the mitochondrial-assisted apoptosis pathway contributes to cell killing induced by NCP 2. The inhibitory action of NCP 2 on cancerous cells is further supported by a time dependent cell migration inhibition study. We do believe that the study described herein opens an avenue for extensive further investigation on a new generation of crystalline functional nanomaterials based on simple molecular components.

Figure 10. Assessment of mitochondrial dependent apoptosis using immunofluorescence microscopy. HCT 116 cells were treated with 25 μg/mL of NCP 2 (IC50) for 24 h followed by immunofluorescence staining. Representative fluorescence microscopy images of Bcl2 and Bax which were labeled with FITC and PE, respectively. Nuclei were counter stained with DAPI. Scale bars: 10 μm. Images were acquired for each fluorescence channel, using suitable filters with a 60× objective.


Materials and Methods. All the chemicals (metal salt and coligands) were purchased from commercial sources and used without further purification. Solvents were of Spectral grade and used without any further distillation. The ligand 5N3H2-IPA was synthesized following the literature method.68 Elemental analyses (C, H & N) were performed using a PerkinElmer 240C analyzer. FT-IR spectra (4000−400 cm−1) were recorded on PerkinElmer RXI FT-IR spectrophotometer using KBr disk. TGA analyses were carried out on a SDT Q Series 600 Universal VA.2E TA Instruments. The photoluminescence spectra of the NCPs were recorded on PerkinElmer LS55 Fluorescence Spectrometer. Scanning Electron Microscopy (SEM) of NCPs was carried out in with JEOL JSM-6700F field-emission microscope. DLS studies of the NCPs were carried out in a DLS Malvern particle size analyzer (model no. ZEN 3690 ZETASIZER NANO ZS 90). Synthesis of [{Zn(μ2-H2O)0.5(5N3-IPA)(2,2′-bpe)}]∞ (1). The ligand 5-azidoisophthalic acid (5N3−H2IPA) (0.1 mmol, 20.7 mg) and the coligand 2,2′-bipydine (2,2′-bpe) (0.1 mmol,15.6 mg) were dissolved in a mixture of 1 mL DMF and 2 mL MeOH mixture. Two mL aqueous solution of Zn(NO3)2 (0.1 mmol, 25.3 mg) was added to it dropwise with stirring. The resultant mixture was taken in a sealed container and heated to 85°C for 2 days. Upon slow cooling to room temperature transparent block shaped crystals were obtained (Yield 52% based on 5N3H2-IPA) which was then filtered, washed with

of Bax expression activates caspase, and cell death occurs through an event known as mitochondrial outer membrane permeabilization.66 This data suggested that NCP 2 induced cytotoxicity of HCT 116 was dependent upon the mitochondrial-assisted apoptosis pathway. NCP 2 Induced Suppression in Cell Migration of HCT 116 Cells. Cell migration is a central activity to all normal cells. However, cancerous cells exhibit uncontrolled cell migration. To detect the inhibitory action of NCP 2 on cell migration of HCT 116, the scratch assay was carried out.67 When treated with 25 μg/mL of NCP 2, cell migration of HCT 116 was reduced in a time-dependent manner (0, 12, and 24 h). The result also showed the number of cells was also significantly reduced in the denuded area, suggesting that NCP 2 could G

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry acetone and dried under air. FT-IR (4000−400 cm−1): 3414 (brs), 3081 (w), 2930 (w), 2117 (s), 1632 (s), 1570 (s), 1447 (s), 1353 (s), 1095 (w), 1024 (w), 930 (w), 889 (w), 776 (s), 693 (w), 415 (s). Elemental Analysis: C36H24N10O9Zn2 (871.43): Calcd C 49.62, H 2.78, N 16.07; found C 49.53, H 2.55, N 15.99. Analyzing the thermo gravimetric data plot first weight loss of 2.43% was started at temperature 85°C (Figure S11 in Supporting Information). This can be attributed to the loss of coordinated water molecule (calculated 2.06%) from the asymmetric unit of the CP. The loss of 15.6% weight at a temperature regime 192°C-285°C was due to the dissociation of a N2 molecule from the azide moiety (calculated 6.42%), whereas the excess portion is due to the disintegration of some other part of the molecule at such a higher temperature. This data well reconciled the structural analysis of 1. Synthesis of [{Zn(μ2-H2O)0.5(5N3-IPA)(1,10-phen)}]∞ (2). 2 was synthesized following similar procedure as that of 1 only instead of 2,2′-bpe, 1,10-phenanthroline (1,10-phen) (0.1 mmol, 18.02 mg) was used. Transparent block shaped crystals were obtained (Yield 43.7% based on 5N3H2-IPA) which were further washed with acetone and dried in air. IR (4000−400 cm−1): 3425 (brs), 3079 (vw), 2114 (s), 1633 (s), 1633 (s), 1548 (s), 1349 (s), 1097 (w), 867 (s), 783 (s), 719 (s), 562 (s), 469 (w). Elemental Analysis: C40H24N10O9Zn2 (919.47): Calcd C 52.25, H 2.63, N 15.23; found C 52.07, H 2.49, N 15.09. Analyzing the thermo gravimetric data plot first weight loss of 2.61% was started at temperature around 82°C (Figure S12 in Supporting Information). This can be accredited to the loss of coordinated water molecule from the asymmetric unit of 2 (calculated 1.95%). The loss of 7.59% weight at a temperature regime 184°C235°C was due to the disintegration of a N2 molecule (calculated 6.09%) from the azide moiety. This data well reconciled the structural analysis of 2. Preparation of [{Zn(5N3-IPA)(1,2-bpe)}]∞ (3). 3 was synthesized following the similar procedure as that of 1 only by changing 2,2′-bpe with 1,2-bpe (0.1 mmol, 18.40 mg). Yellow colored block shaped crystals were obtained (Yield 54.3% based on 5N3H2-IPA) which were further washed with acetone and dried. IR (4000−400 cm−1): 3425 (brs), 3079 (vw), 2220 (w), 2114 (s), 1633 (s), 1495 (s), 1338 (w), 1035 (s), 929 (s), 825 (s), 783 (s), 604 (s), 541 (s), 478 (s). Elemental Analysis: C20H15N5O4Zn (454.76): Calcd C 52.82, H 3.32, N 15.40; found C 52.65, H 3.44, N 15.29. Analyzing the thermo gravimetric data plot weight loss of 5.98% was observed within the temperature range of 162°C-235°C (Figure S13 in Supporting Information). This can be accredited to the disintegration of a N2 molecule (calculated 6.15%) from the azide moiety. This data well reconciled the structural analysis of 3. Preparation of [{Zn(5N3-IPA)(1,2-bpey)}]∞ (4). 4 was synthesized following the similar procedure as that of 1 only 1,2-bpey (0.1 mmol, 18.22 mg) is used instead of 2,2′-bpe. Transparent block shaped crystals were obtained (Yield 61.4% based on 5N3H2-IPA) which were further washed with acetone and dried under air. IR (4000−400 cm−1): 3825 (w), 3752 (w), 3427 (brs), 2123 (s), 1616 (s), 1366 (s), 1024 (w), 774 (s), 546 (s). Elemental Analysis: C20H13N5O4Zn (452.74): Calcd C 53.06, H 2.89, N 15.47, found C 53.23, H 2.71, N 15.59. Analyzing the thermo gravimetric data plot weight loss of 6.00% was observed within the temperature range of 145°C-256°C (Figure S14 in Supporting Information). This can be accredited to the disintegration of a N2 molecule (calculated 6.18%) from the azide moiety. This data well reconciled the structural analysis of 4. Preparation of [{Zn(H2O)(5N3-IPA)(4,4′-tme)}(H2O)0.5]∞ (5). 5 was synthesized following the similar procedure as that of 1 by changing 2,2′-bpe with 4,4′-tme (0.1 mmol, 19.82 mg). Transparent block shaped crystals were obtained (Yield 42.9% based on 5N3H2-IPA which were further washed with acetone and dried under air. IR (4000−400 cm−1): 3508 (brs), 2931 (s) 2106 (s), 1623 (s), 1560 (s), 1375 (s) 1200 (w), 1025 (w), 788 (s), 725 (s), 511 (s). Elemental Analysis: C42H40N10O11Zn2 (991.62): Calcd C 50.87, H 4.07, N 14.13; found C 51.09, H 3.92, N 14.27. Analyzing the thermo gravimetric data plot first weight loss of 4.36% was observed within the temperature range of 83°C-160°C

(Figure S15 in Supporting Information). This can be accredited to the loss of one coordinated and another lattice occluded water molecule from the asymmetric unit of the CP (calculated 5.44%). The loss of 6.81% weight at a temperature regime 160°C-251°C (calculated 5.64%) was due to the disintegration of a N2 molecule from the azide moiety. This data well reconciled the structural analysis of 5. Caution! Azides are potentially explosive and should be handled in small amounts and with proper precautions. Synthesis of NCPs by Hand Ground Method. A small amount (nearly 50−60 mg) of the synthesized CPs (1-5) was taken separately in a mortar. It was then being ground manually for 30 min by using a pestle. The produced nano sized CPs were directly used for several studies that are mentioned here. Cell Culture. HCT 116 cells were procured from National Centre for Cell Sciences cell repository (NCCS, Pune, India). Cells were cultured in DMEM (Dulbecco’s modified Eagle’s medium) supplemented with 10% (v/v) heat-inactivated FBS (Fetal bovine serum), 100 U/mL penicillin and 100 μg/mL streptomycin, at 37 °C in a humidified 5% CO2 environment.69 Determination of Cell Viability Using MTT assay. Cell viability was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay.64 Briefly, HCT 116 cells (1 × 106 cells/ well) were cultured with different concentration of NCPs 1-5 (5, 10, 20, 40, 60, 80 and, 100 μg/mL) for 24 h. After treatment cells were incubated with MTT solution (5 mg/mL) at 37 °C for 4 h and then the medium was removed following the addition of DMSO which was incubated for 15 min. The resultant absorbance was measured with a microplate reader (Molecular Devices, CA, USA) at a wavelength of 570 nm. All experiments were analyzed in triplicate. Determination of Protein Expression Using Immunofluorescence. Briefly, treated cells along with the control cells were fixed with paraformaldehyde (4%) following the permeabilization with Triton X-100. Then the cells were blocked with BSA (5%) for 2 h. Cells were then incubated with anti-Bax-PE and anti-Bcl2-FITC conjugated antibody (dilution 1:700) at 4 °C for overnight. DAPI was used for nuclear staining and the resultant images were captured by an FSX100 microscope (Olympus, Tokyo, Japan).70 In Vitro Cell Migration Assay. Cells were grown in 12-well plates for 24 h. A straight scratch was made on the confluence cell using a pipet tip following the washing with PBS for three times. Then the cells were treated with NCP 2 in serum-free DMEM medium. After incubating for 0, 12, and 24 h, the gap width of scratch repopulation was measured and recorded which was then compared with the initial gap size at 0 h. The gap was measured using ImageJ image processing program and the size of the denuded area was determined at each time point from the digital images.62 Preparation of the SEM Sample. All the NCPs (1-5) were dispersed in DMSO through sonication for about 20 min. The dispersed solutions were drop-casted on separate glass disks. The disks were dried under air at room temperature for 2 days and subjected to SEM experiment to record the corresponding images. Preparation of Sample for DLS Experiment. One mg of each nanoscale CPs was dispersed in 4 mL DMSO. The dispersed solutions were taken in a quartz cuvette and subjected to DLS experiment to get the radius distribution of the solvent coated NCPs. A time dependent DLS study was performed for 2 following the similar method to check the biostability of the NCPs. In that case dispersion media is replaced by phosphate buffer saline (PBS, pH = 7.4) and DLS data were collected just after dispersion, after 6, 12, 24, 48, 72 h. X-ray Crystallography. Single-crystal X-ray diffraction data were collected using Mo Kα (λ = 0.7107 Å) radiation on a BRUKER APEX II diffractometer equipped with a CCD area detector. Data collection, data reduction, and structure solution refinement were carried out using APEX II. All the structures were solved by direct methods and refined in a routine manner. In all the cases, the non hydrogen atoms are treated anisotropically except for disordered atoms. Whenever possible, the hydrogen atoms were located on a difference Fourier map and refined. In other cases, the hydrogen atoms were geometrically fixed. Crystallographic data are summarized in Table 1 in the manuscript. CIF files for the structures reported in this paper have H

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry been deposited with the Cambridge Crystallographic Data Centre (CCDC). CCDC- 1587101−1587105 contains the supplementary crystallographic data for the paper. Copies of the data can be obtained, free of charge on application to the CCDC, 12 Union Road, Cambridge, CB2 1EZ UK [Fax: 44 (1233) 336 033 e-mail: deposit@]. Powder X-ray Diffraction. Powder X-ray diffraction (PXRD) measurements were performed on a Bruker AXS D8 Advance X-ray (Cu Kα radiation, λ = 1.5406 Å) diffractometer in the 5−35° 2θ range using a 0.02° step size per second. The sample was prepared by making a thin film from the finely powdered sample (∼30 mg) over a glass slide.

(4) Perry IV, J. J.; Perman, J. A.; Zaworotko, M. J. Design and Synthesis of Metal−organic Frameworks Using Metal−organic Polyhedra as Supermolecular Building Blocks. Chem. Soc. Rev. 2009, 38, 1400−1417. (5) Hoskins, B. F.; Robson, R. Infinite Polymeric Frameworks Consisting of Three Dimensionally Linked Rod-like Segments. J. Am. Chem. Soc. 1989, 111, 5962−5964. (6) Murray, L. J.; Dincă, M.; Long, J. R. Hydrogen Storage in Metal− organic Frameworks. Chem. Soc. Rev. 2009, 38, 1294−1314. (7) Furukawa, H.; Yaghi, O. M. Storage of Hydrogen, Methane, and Carbon Dioxide in Highly Porous Covalent Organic Frameworks for Clean Energy Applications. J. Am. Chem. Soc. 2009, 131, 8875−8883. (8) Xiang, S.; Huang, J.; Li, L.; Zhang, J.; Jiang, L.; Kuang, X.; Su, C. Y. Nanotubular Metal-Organic Frameworks with High Porosity Based on T-Shaped Pyridyl Dicarboxylate Ligands. Inorg. Chem. 2011, 50, 1743−1748. (9) Eddaoudi, M.; Kim, J.; Rosi, N.; Vodak, D.; Wachter, J.; Keeffe, M. O.; Yaghi, O. M.; Eddaoudi, M.; Kimrn, J.; Rosi, N.; Yaghil, O. M. Systematic Design of Pore Size and Functionality in Isoreticular MOFs and Their Application in Methane Storage. Science 2002, 295, 469− 472. (10) D’Alessandro, D. M.; Smit, B.; Long, J. R. Carbon Dioxide Capture: Prospects for New Materials. Angew. Chem., Int. Ed. 2010, 49, 6058−6082. (11) Ma, S.; Zhou, H.-C. Gas Storage in Porous Metal-Organic Frameworks for Clean Energy Applications. Chem. Commun. 2010, 46, 44−53. (12) Li, J. R.; Sculley, J.; Zhou, H. C. Metal-Organic Frameworks for Separations. Chem. Rev. 2012, 112, 869−932. (13) Bloch, E. D.; Queen, W. L.; Krishna, R.; Zadrozny, J. M.; Brown, C. M.; Long, J. R. Hydrocarbon Separations in a Metal-Organic Framework with Open iron(II) Coordination Sites. Science 2012, 335, 1606−1610. (14) Nurchi, V. M.; Crisponi, G.; Villaescusa, I. Chemical Equilibria in Wastewaters during Toxic Metal Ion Removal by Agricultural Biomass. Coord. Chem. Rev. 2010, 254, 2181−2192. (15) Custelcean, R.; Moyer, B. A. Anion Separation with MetalOrganic Frameworks. Eur. J. Inorg. Chem. 2007, 2007, 1321−1340. (16) Adarsh, N. N.; Kumar, D. K.; Dastidar, P. Zn(II) Metal−organic Frameworks (MOFs) Derived from a Bis-Pyridyl-Bis-Urea Ligand: Effects of Crystallization Solvents on the Structures and Anion Binding Properties. CrystEngComm 2008, 10, 1565. (17) Wen, G. X.; Wu, Y. P.; Dong, W. W.; Zhao, J.; Li, D. S.; Zhang, J. An Ultrastable Europium(III)-Organic Framework with the Capacity of Discriminating Fe2+/Fe3+ Ions in Various Solutions. Inorg. Chem. 2016, 55, 10114−10117. (18) Corma, A.; García, H.; Llabrés i Xamena, F. X. Engineering Metal Organic Frameworks for Heterogeneous Catalysis. Chem. Rev. 2010, 110, 4606−4655. (19) Yoon, M.; Srirambalaji, R.; Kim, K. Homochiral Metal-Organic Frameworks for Asymmetric Heterogeneous Catalysis. Chem. Rev. 2012, 112, 1196−1231. (20) Wang, S.; Li, L.; Zhang, J.; Yuan, X.; Su, C.-Y. Anion-Tuned Sorption and Catalytic Properties of a Soft Metal−organic Solid with Polycatenated Frameworks. J. Mater. Chem. 2011, 21, 7098−7104. (21) Lee, J.; Farha, O. K.; Roberts, J.; Scheidt, K. A.; Nguyen, S. T.; Hupp, J. T. Metal−organic Framework Materials as Catalysts. Chem. Soc. Rev. 2009, 38, 1450−1459. (22) Zhang, J.; Wang, X.; He, L.; Chen, L.; Su, C.-Y.; James, S. L. Metal−organic Gels as Functionalisable Supports for Catalysis. New J. Chem. 2009, 33, 1070−1075. (23) Gole, B.; Sanyal, U.; Mukherjee, P. S. A Smart Approach to Achieve an Exceptionally High Loading of Metal Nanoparticles Supported by Functionalized Extended Frameworks for Efficient Catalysis. Chem. Commun. 2015, 51, 4872−4875. (24) Gole, B.; Sanyal, U.; Banerjee, R.; Mukherjee, P. S. High Loading of Pd Nanoparticles by Interior Functionalization of MOFs for Heterogeneous Catalysis. Inorg. Chem. 2016, 55, 2345−2354.


* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b00237. FT-IR, TGA, PXRD, UV−vis spectra, quantum yield calculations, biological studies, DLS data, EDX analysis, ORTEP diagram, SEM images, and selected bond angles and bond lengths table for all the CPs 1−5 (PDF) Accession Codes

CCDC 1587101−1587105 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.


Corresponding Author

*E-mail: [email protected]. ORCID

Debasis Das: 0000-0003-4570-7168 Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS D.D. thanks Dr. Krishna Das Saha, Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, for providing help in the biological analysis of the samples. The authors duly acknowledge CRNN (CU) for providing the SEM facilities. Somali Mukherjee thanks CSIR, New Delhi, for the research fellowship (CSIR Grant No: 09/028(1009)/2017-EMR-I). S.G. thanks SERB for the National Post Doctoral Fellowship (Sanction No: PDF/ 2016/000566). Somali Mukherjee and S.G. thank Rumana Parveen, IACS, for useful scientific discussions. SCXRD data were collected in the DBT-funded X-ray diffraction facility under the CEIB program (BT/01/CEIB/11/v/13) in the Department of Organic Chemistry, IACS.


(1) James, S. L. Metal-Organic Frameworks. Chem. Soc. Rev. 2003, 32, 276−288. (2) Banerjee, R.; Phan, A.; Wang, B.; Knobler, C.; Furukawa, H.; O’Keeffe, M.; Yaghi, O. M. High-Throughput Synthesis of Zeolitic Imidazolate Frameworks and Application to CO2 Capture. Science 2008, 319, 939−943. (3) Zhou, H.-C.; Kitagawa, S. Metal−Organic Frameworks (MOFs). Chem. Soc. Rev. 2014, 43, 5415−5418. I

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry (25) Wu, Y. P.; Zhou, W.; Zhao, J.; Dong, W. W.; Lan, Y. Q.; Li, D. S.; Sun, C.; Bu, X. Surfactant-Assisted Phase-Selective Synthesis of New Cobalt MOFs and Their Efficient Electrocatalytic Hydrogen Evolution Reaction. Angew. Chem., Int. Ed. 2017, 56, 13001−13005. (26) Xu, G. W.; Wu, Y. P.; Dong, W. W.; Zhao, J.; Wu, X. Q.; Li, D. S.; Zhang, Q. A Multifunctional Tb-MOF for Highly Discriminative Sensing of Eu3+/Dy3+ and as a Catalyst Support of Ag Nanoparticles. Small 2017, 13, 1−8. (27) Hu, Z.; Deibert, B. J.; Li, J. Luminescent Metal−organic Frameworks for Chemical Sensing and Explosive Detection. Chem. Soc. Rev. 2014, 43, 5815−5840. (28) Kreno, L. E.; Leong, K.; Farha, O. K.; Allendorf, M.; Van Duyne, R. P.; Hupp, J. T. Metal-Organic Framework Materials as Chemical Sensors. Chem. Rev. 2012, 112, 1105−1125. (29) Liu, D.; Lu, K.; Poon, C.; Lin, W. Metal-Organic Frameworks as Sensory Materials and Imaging Agents. Inorg. Chem. 2014, 53, 1916− 1924. (30) Wallace, K. J.; Belcher, W. J.; Turner, D. R.; Syed, K. F.; Steed, J. W. Slow Anion Exchange, Conformational Equilibria, and Fluorescent Sensing in Venus Flytrap Aminopyridinium-Based Anion Hosts. J. Am. Chem. Soc. 2003, 125, 9699−9715. (31) Gole, B.; Bar, A. K.; Mukherjee, P. S. arathi. Modification of Extended Open Frameworks with Fluorescent Tags for Sensing Explosives: Competition between Size Selectivity and Electron Deficiency. Chem. - Eur. J. 2014, 20, 2276−2291. (32) Anbu, S.; Kamalraj, S.; Jayabaskaran, C.; Mukherjee, P. S. Naphthalene Carbohydrazone Based dizinc(II) Chemosensor for a Pyrophosphate Ion and Its DNA Assessment Application in Polymerase Chain Reaction Products. Inorg. Chem. 2013, 52, 8294− 8296. (33) Wang, C.; Zhang, T.; Lin, W. Rational Synthesis of Noncentrosymmetric Metal-Organic Frameworks for Second-Order Nonlinear Optics. Chem. Rev. 2012, 112, 1084−1104. (34) Medishetty, R.; Zaręba, J. K.; Mayer, D.; Samoć, M.; Fischer, R. A. Nonlinear Optical Properties, Upconversion and Lasing in Metal− organic Frameworks. Chem. Soc. Rev. 2017, 46, 4976−5004. (35) Rieter, W. J.; Pott, K. M.; Taylor, K. M.; Lin, W. Nanoscale Coordination Polymers for Platinum-Based Anticancer Drug Delivery. J. Am. Chem. Soc. 2008, 130, 11584−11585. (36) Rieter, W. J.; Taylor, K. M. L.; An, H.; Lin, W.; Lin, W. Nanoscale Metal-Organic Frameworks as Potential Multimodal Contrast Enhancing Agents. J. Am. Chem. Soc. 2006, 128, 9024−9025. (37) Taylor, K. M. L.; Jin, A.; Lin, W. Surfactant-Assisted Synthesis of Nanoscale Gadolinium Metal-Organic Frameworks for Potential Multimodal Imaging. Angew. Chem., Int. Ed. 2008, 47, 7722−7725. (38) Horcajada, P.; Chalati, T.; Serre, C.; Gillet, B.; Sebrie, C.; Baati, T.; Eubank, J. F.; Heurtaux, D.; Clayette, P.; Kreuz, C.; Chang, J. S.; Hwang, Y. K.; Marsaud, V.; Bories, P. N.; Cynober, L.; Gil, S.; Férey, G.; Couvreur, P.; Gref, R. Porous Metal-Organic-Framework Nanoscale Carriers as a Potential Platform for Drug Deliveryand Imaging. Nat. Mater. 2010, 9, 172−178. (39) Haque, E.; Khan, N.; Park, H. J.; Jhung, S. H. Synthesis of a Metal-Organic Framework Material, Iron Terephthalate, by Ultrasound, Microwave, and Conventional Electric Heating: A Kinetic Study. Chem. - Eur. J. 2010, 16, 1046−1052. (40) Cheng, M.; Cuda, G.; Bunimovich, Y.; Gaspari, M.; Heath, J.; Hill, H.; Mirkin, C.; Nijdam, A.; Terracciano, R. Nanotechnologies for Biomolecular Detection and Medical Diagonistic. Curr. Opin. Chem. Biol. 2006, 10, 11−19. (41) Toublan, F. J. J.; Boppart, S.; Suslick, K. S. Tumor Targeting by Surface-Modified Protein Microspheres. J. Am. Chem. Soc. 2006, 128, 3472−3473. (42) An, B. K.; Kwon, S. K.; Jung, S. D.; Park, S. Y. Enhanced Emission and Its Switching in Fluorescent Organic Nanoparticles. J. Am. Chem. Soc. 2002, 124 (48), 14410−14415. (43) Daniel, M. C. M.; Astruc, D. Gold Nanoparticles: Assembly, Supramolecular Chemistry, Quantum-Size Related Properties and Applications toward Biology, Catalysis and Nanotechnology. Chem. Rev. 2004, 104, 293−346.

(44) Kim, S. W.; Zimmer, J. P.; Ohnishi, S.; Tracy, J. B.; Frangioni, J. V.; Bawendi, M. G. Engineering InAsxP1-x/InP/ZnSe III-V Alloyed Core/shell Quantum Dots for the near-Infrared. J. Am. Chem. Soc. 2005, 127, 10526−10532. (45) Wang, E. C.; Wang, A. Z. Nanoparticles and Their Applications in Cell and Molecular Biology. Integr. Biol. 2014, 6, 9−26. (46) McKinlay, A. C.; Morris, R. E.; Horcajada, P.; Férey, G.; Gref, R.; Couvreur, P.; Serre, C. BioMOFs: Metal-Organic Frameworks for Biological and Medical Applications. Angew. Chem., Int. Ed. 2010, 49, 6260−6266. (47) Lin, W.; Rieter, W. J.; Taylor, K. M. L. Modular Synthesis of Functional Nanoscale Coordination Polymers. Angew. Chem., Int. Ed. 2009, 48, 650−658. (48) He, C.; Liu, D.; Lin, W. Nanomedicine Applications of Hybrid Nanomaterials Built from Metal-Ligand Coordination Bonds: Nanoscale Metal-Organic Frameworks and Nanoscale Coordination Polymers. Chem. Rev. 2015, 115, 11079−11108. (49) He, C.; Duan, X.; Guo, N.; Chan, C.; Poon, C.; Weichselbaum, R. R.; Lin, W. Core-Shell Nanoscale Coordination Polymers Combine Chemotherapy and Photodynamic Therapy to Potentiate Checkpoint Blockade Cancer Immunotherapy. Nat. Commun. 2016, 7, 1−12. (50) He, C.; Poon, C.; Chan, C.; Yamada, S. D.; Lin, W. Nanoscale Coordination Polymers Codeliver Chemotherapeutics and Sirnas to Eradicate Tumors of Cisplatin-Resistant Ovarian Cancer. J. Am. Chem. Soc. 2016, 138, 6010−6019. (51) Lu, K.; He, C.; Lin, W. A Chlorin-Based Nanoscale MetalOrganic Framework for Photodynamic Therapy of Colon Cancers. J. Am. Chem. Soc. 2015, 137, 7600−7603. (52) Wang, Y.-M.; Liu, W.; Yin, X.-B. Multifunctional Mixed-Metal Nanoscale Coordination Polymers for Triple-Modality ImagingGuided Photodynamic Therapy. Chem. Sci. 2017, 8, 3891−3897. (53) Qi, X.; Chang, Z.; Zhang, D.; Binder, K. J.; Shen, S.; Huang, Y. Y. S.; Bai, Y.; Wheatley, A. E. H.; Liu, H. Harnessing SurfaceFunctionalized Metal-Organic Frameworks for Selective Tumor Cell Capture. Chem. Mater. 2017, 29, 8052−8056. (54) Sarkar, K.; Dastidar, P. Nanoscale Mn II -Coordination Polymers for Cell Imaging and Heterogeneous Catalysis. Chem. Eur. J. 2016, 22, 18963−18974. (55) Yang, L.; Powell, D. R.; Houser, R. P. Structural Variation in Copper( i) Complexes with Pyridylmethylamide Ligands: Structural Analysis with a New Four-Coordinate Geometry Index, τ 4. Dalt. Trans. 2007, 955−964. (56) Addison, A. W.; Rao, T. N. Synthesis, Structure, and Spectroscopic Properties. J. Chem. Soc., Dalton Trans. 1984, 1349− 1356. (57) Blatov, V. A. Nanocluster Analysis of Intermetallic Structures with the Program Package TOPOS. Struct. Chem. 2012, 23, 955−963. (58) Blatov, V. A.; Proserpio, D. M. Periodic-Graph Approaches in Crystal Structure Prediction. In Modern Methods of Crystal Structure Prediction; 2010; pp 1−28. (59) Blatov, V. A.; O’Keeffe, M.; Proserpio, D. M. Vertex-, Face-, Point-, Schläfli-, and Delaney-Symbols in Nets, Polyhedra and Tilings: Recommended Terminology. CrystEngComm 2010, 12, 44−48. (60) Alexandrov, E. V.; Blatov, V. A.; Kochetkov, A. V.; Proserpio, D. M. Underlying Nets in Three-Periodic Coordination Polymers: Topology, Taxonomy and Prediction from a Computer-Aided Analysis of the Cambridge Structural Database. CrystEngComm 2011, 13, 3947−3958. (61) O’Keeffe, M.; Yaghi, O. M. Deconstructing the Crystal Structures of Metal Organic Frameworks. Chem. Rev. 2012, 112, 675−702. (62) Reddy, L. S.; Bhogala, B. R.; Nangia, A. The Rare 42.63.8 Network and a Chiral, Trigonal Net in Crystal Structures of 1,3,5tris(4-Pyridyl)benzenes. CrystEngComm 2005, 7, 206−209. (63) Qin, L.; Zeng, S. Y.; Zuo, W. J.; Liu, Q. H.; Li, J.; Ni, G.; Wang, Y. Q.; Zhang, M. D. One Neutral Metal−organic Framework with an Unusual Dmp Topology for Adsorption of Dyes. Polyhedron 2017, 121, 231−235. J

DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX


Inorganic Chemistry (64) Liu, S.; Sun, Z.; Chu, P.; Li, H.; Ahsan, A.; Zhou, Z.; Zhang, Z.; Sun, B.; Wu, J.; Xi, Y.; Han, G.; Lin, Y.; Peng, J.; Tang, Z. EGCG Protects against Homocysteine-Induced Human Umbilical Vein Endothelial Cells Apoptosis by Modulating Mitochondrial-Dependent Apoptotic Signaling and PI3K/Akt/eNOS Signaling Pathways. Apoptosis 2017, 22, 672−680. (65) Peddi, V. R.; Wiseman, A.; Chavin, K.; Slakey, D. Review of Combination Therapy with mTOR Inhibitors and Tacrolimus Minimization after Transplantation. Transplant. Rev. 2013, 27, 97− 107. (66) Tait, S. W. G.; Green, D. R. Mitochondrial Regulation of Cell Death. Cold Spring Harbor Perspect. Biol. 2013, 5, 1−15. (67) Liang, C. C.; Park, A. Y.; Guan, J. L. In Vitro Scratch Assay: A Convenient and Inexpensive Method for Analysis of Cell Migration in Vitro. Nat. Protoc. 2007, 2, 329−333. (68) Ganguly, S.; Pachfule, P.; Bala, S.; Goswami, A.; Bhattacharya, S.; Mondal, R. Azide-Functionalized Lanthanide-Based Metal-Organic Frameworks Showing Selective CO2gas Adsorption and Postsynthetic Cavity Expansion. Inorg. Chem. 2013, 52, 3588−3590. (69) Bhanja, P.; Mishra, S.; Manna, K.; Mallick, A. Das Saha, K.; Bhaumik, A. Covalent Organic Framework Material Bearing Phloroglucinol Building Units as a Potent Anticancer Agent. ACS Appl. Mater. Interfaces 2017, 9, 31411−31423. (70) Manna, K.; Das, U.; Das, D.; Kesh, S. B.; Khan, A.; Chakraborty, A.; Dey, S. Naringin Inhibits Gamma Radiation-Induced Oxidative DNA Damage and Inflammation, by Modulating p53 and NF-κB Signaling Pathways in Murine Splenocytes. Free Radical Res. 2015, 49, 422−439.


DOI: 10.1021/acs.inorgchem.8b00237 Inorg. Chem. XXXX, XXX, XXX−XXX